This invention relates to compositions and methods for delivery of drugs, especially peptide drugs, to a warm-blooded animal by transmucosal administration and particularly through the buccal mucosa of the oral cavity. More particularly, the invention relates to compositions and methods for buccal delivery of glucagon-like insulinotropic peptides (GLIPs) into the body.
Traditionally there has been very little work evaluating membranes of the oral cavity as sites of drug administration. Both the buccal and sublingual membranes offer advantages over other routes of administration. For example, drugs administered through the buccal and sublingual routes have a rapid onset of action, reach high levels in the blood, avoid the first-pass effect of hepatic metabolism, and avoid exposure of the drug to fluids of the gastrointestinal tract. Additional advantages include easy access to the membrane sites so that the drug can be applied, localized, and removed easily. Further, there is good potential for prolonged delivery through the buccal membrane. M. Rathbone & J. Hadgraft, 74 Int'l J. of Pharmaceutics 9 (1991). Administration through the buccal mucosa may be better accepted than rectal dosing, for example, and generally avoids local toxic effects, such as has been a problem in nasal administration. B. Aungst & N. Rogers, 53 Int'l J. Pharmaceutics 227, 228 (1989).
The sublingual route has received far more attention than has the buccal route. The sublingual mucosa includes the membrane of the ventral surface of the tongue and the floor of the mouth, whereas the buccal mucosa constitutes the lining of the cheek and lips. The sublingual mucosa is relatively permeable, thus giving rapid absorption and acceptable bioavailabilities of many drugs. Further, the sublingual mucosa is convenient, easily accessible, and generally well accepted. This route has been investigated clinically for the delivery of a substantial number of drugs. It is the traditional route for administration of nitroglycerin and is also used for buprenorphine and nifedipine. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1 (1992). The sublingual mucosa is not well suited to sustained-delivery systems, however, because it lacks an expanse of smooth and relatively immobile mucosa suitable for attachment of a retentive delivery system.
The buccal mucosa is less permeable than the sublingual mucosa, and the rapid absorption and high bioavailabilities seen with sublingual administration of drugs is not generally provided to the same extent by the buccal mucosa. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1, 2 (1992). The permeability of the oral mucosae is probably related to the physical characteristics of the tissues. The sublingual mucosa is thinner than the buccal mucosa, thus permeability is greater for the sublingual tissue. The palatal mucosa is intermediate in thickness, but is keratinized and thus less permeable, whereas the sublingual and buccal tissues are not keratinized. The buccal mucosa, however, appears well suited to attachment of retentive delivery systems.
The ability of molecules to permeate through the oral mucosae also appears to be related to molecular size, lipid solubility, and ionization. Small molecules, less than about 300 daltons, appear to cross the mucosae rapidly. As molecular size increases, however, permeability decreases rapidly. Lipid-soluble compounds are more permeable through the mucosae than are non-lipid-soluble molecules. In this regard, the relative permeabilities of molecules seems to be related to their partition coefficients. The degree of ionization of molecules, which is dependent on the pK.sub.a of the molecule and the pH at the membrane surface, also greatly affects permeability of the molecules. Maximum absorption occurs when molecules are unionized or neutral in electrical charge; absorption decreases as the degree of ionization increases. Therefore, charged macromolecular drugs present the biggest challenge to absorption through the oral mucosae.
Substances that facilitate the transport of solutes across biological membranes, penetration enhancers, are well known in the art for administering drugs. V. Lee et al., 8 Critical Reviews in Therapeutic Drug Carrier Systems 91 (1991) hereinafter "Critical Reviews"!. Penetration enhancers can be categorized as (a) chelators (e.g., EDTA, citric acid, salicylates), (b) surfactants (e.g., sodium dodecyl sulfate (SDS)), (c) non-surfactants (e.g., unsaturated cyclic ureas), (d) bile salts (e.g., sodium deoxycholate, sodium taurocholate), and (e) fatty acids (e.g., oleic acid, acylcarnitines, mono- and diglycerides). The efficacy of enhancers in transporting both peptide and nonpeptide drugs across membranes seems to be positively correlated with the enhancer's hydrophobicity. Critical Reviews at 112. For example, the efficacy of bile salts in enhancing the absorption of insulin through nasal membranes is positively correlated with the hydrophobicity of the bile salts' steroid structure. Critical Reviews at 115. Thus, the order of effectiveness is deoxycholate&lt;chenodeoxycholate&lt;cholate&lt;ursodeoxycholate. Conjugation of deoxycholate and cholate, but not fusidic acid derivatives, with glycine and taurine does not affect their enhancement potency. Transmucosal intestinal delivery of heparin is not apparent, as measured in terms of prolongation of partial thromboplastin time or release of plasma lipase activity, when administered through the colon of a baboon. However, significant activity is detected when the bile salts, sodium cholate or deoxycholate, are included in the formulation. Critical Reviews at 108.
Various mechanisms of action of penetration enhancers have been proposed. These mechanisms of action, at least for peptide and protein drugs, include (1) reducing the viscosity and/or elasticity of mucus layer, (2) facilitating transcellular transport by increasing the fluidity of the lipid bilayer of membranes, (3) facilitating paracellular transport by altering tight junctions across the epithelial cell layer, (4) overcoming enzymatic barriers, and (5) increasing the thermodynamic activity of the drugs. Critical Reviews at 117-125.
Many penetration enhancers have been tested and found effective in facilitating mucosal drug administration, but hardly any penetration enhanced products have reached the market place. Reasons for this include lack of a satisfactory safety profile respecting irritation, lowering of the barrier function, and impairment of the mucociliary clearance protective mechanism. Critical Reviews at 169-70. Further, for an enhancer to function adequately, the enhancer and drug combination is preferably held in position against mucosal tissues for a period of time sufficient to allow enhancer-assisted penetration of the drug across the mucosal membrane. In transdermal and transmucosal technology, this is often accomplished by means of a patch or other device that adheres to the skin layer by means of an adhesive.
Oral adhesives are well known in the art. See, for example, Tsuk et al., U.S. Pat. No. 3,972,995; Lowey, U.S. Pat. No. 4,259,314; Lowey, U.S. Pat. 4,680,323; Yukimatsu et al., U.S. Pat. No. 4,740,365; Kwiatek et al., U.S. Pat. No. 4,573,996; Suzuki et al., U.S. Pat. No. 4,292,299; Suzuki et al., U.S. Pat. No. 4,715,369; Mizobuchi et al., U.S. Pat. No. 4,876,092; Fankhauser et al., U.S. Pat. No. 4,855,142; Nagai et al., U.S. Pat. No. 4,250,163; Nagai et al., U.S. Pat. No. 4,226,848; Browning, U.S. Pat. No. 4,948,580; Schiraldi et al.,U.S. Reissue Pat. No. Re.33,093; and J. Robinson, 18 Proc. Intern. Symp. Control. Rel. Bioact. Mater. 75 (1991). Typically, these adhesives consist of a matrix of a hydrophilic, e.g., water soluble or swellable, polymer or mixture of polymers that can adhere to a wet mucous surface. These adhesives may be formulated as ointments, thin films, tablets, troches, and other forms. Often, these adhesives have had medicaments mixed therewith to effectuate slow release or local delivery of a drug. Some, however, have been formulated to permit adsorption through the mucosa into the circulatory system of the individual.
Glucagon-like insulinotropic peptides, e.g. GLP-1(7-36)amide, are antidiabetogenic agents being investigated for treatment of diabetes mellitus that have heretofore been administered intravenously, subcutaneously, or by some other invasive route, and are too large for transdermal delivery. Diabetes mellitus afflicts nearly 15 million people in the United States. About 15 percent have insulin-dependent diabetes (IDDM; type 1 diabetes), which is believed to be caused by autoimmune destruction of pancreatic islet beta cells. In such patients, insulin therapy is essential for life. About 80% of patients have non-insulin-dependent diabetes (NIDDM; type 2 diabetes), a heterogeneous disorder characterized by both impaired insulin secretion and insulin resistance. A few patients who appear to have NIDDM may actually have a slowly progressive form of IDDM and eventually become dependent on insulin. Most patients with NIDDM, however, can be treated without insulin. They are usually overweight and have the insulin resistance of obesity superimposed on the insulin resistance intrinsic to the disease. Weight loss, especially early in the disease, can restore normal glucose levels in the blood of these patients. Their diabetes may develop when the impact of the combined insulin resistances exceeds the ability of their pancreatic beta cells to compensate. Plasma insulin levels in such patients, which are often higher than those in people of normal weight who do not have diabetes, are not appropriate to their obesity and hyperglycemia. People with NIDDM who are not obese may have a primary defect in insulin secretion in which elevations of plasma glucose levels cause not only insulin resistance but also the further deterioration of pancreatic beta cell functioning. J. E. Gerich, Oral Hypoglycemic Agents, 321 N. Engl. J. Med. 1231 (1989).
NIDDM patients are generally treated with diet modifications and sulfonylureas and/or diguanides. H. E. Lebovitz & M. N. Feinglos, Sulfonylurea Drugs: Mechanism of Antidiabetic Action and Therapeutic Usefulness, 1 Diabetes Care 189 (1978). Oral hypoglycemic agents account for about 1 percent of all prescriptions in the United States. J. E. Gerich, 321 N. Engl. J. Med. 1231 (1989). Unfortunately, about 11-36% of NIDDM patients fail to respond well to diet and sulfonylurea therapy after one year of treatment. Within 5-7 years, about half of NIDDM patients receiving sulfonylurea treatment need to start insulin therapy. These patients tend to be resistant to insulin, thus high doses of insulin are administered, which in turn leads to hyperinsulinemia which can play a role in the development of atherosclerosis. D. A. Robertson et al., Macrovascular Disease and Hyperinsulinaemia, in Bailliere's Clinical Endocrinology and Metabolism 407-24 (M. Nattras & P. J. Hale eds., 1988).
In warm-blooded animals and humans, GLIPs stimulate insulin release, lower glucagon secretion, inhibit gastric emptying, and enhance glucose utilization. M. K. Gutniak et al., Antidiabetogenic Effect of Glucagon-Like Peptide-1 (7-36)amide in Normal Subjects and Patients with Diabetes Mellitus, 326 N. Engl. J. Med. 1316 (1992); D. M. Nathan et al., Insulinotropic Action of Glucagonlike Peptide-1-(7(37) in Diabetic and Nondiabetic Subjects, 15 Diabetes Care 270 (1992); M. A. Nauck et al., Normalization of Fasting Hyperglycaemia by Exogenous GlucagonLike Peptide 1 (7-36 amide) in Type 2 (Non-Insulin-Dependent) Diabetic Patients, 36 Diabetologia 741 (1993). Further, these peptide drugs are inherently safe since the insulinotropic effects are strictly glucose dependent, thus limiting the risk of hypoglycemia in response to therapeutic use thereof. M. A. Nauck et al., Normalization of Fasting Hyperglycaemia by Exogenous Glucagon-like Peptide 1 (7-36 amide) in Type 2 (Non-Insulin-Dependent) Diabetic Patients, 36 Diabetologia 741 (1993). These properties make such peptides serious candidates for a therapeutic drug in treatment of non-insulin dependent diabetes mellitus (NIDDM).
GLP-1(7-36)amide is a gastrointestinal hormone processed from the preproglucagon gene. Preproglucagon is a polyprotein hormone precursor comprising a 20-amino acid signal peptide and a 160-amino acid prohormone, proglucagon (PG). PG has been shown to be processed differently in the pancreas and the small intestine of man. C. .O slashed.rskov et al., Pancreatic and Intestinal Processing of Proglucagon in Man, 30 Diabetologia 874 (1987). In the pancreas, the main products are (a) glucagon (PG amino acids 33-61), (b) a glycentin-related pancreatic peptide (GRPP) (PG amino acids 1-30), and (c) a large peptide-designated major proglucagon fragment (MPGF) (PG amino acids 72-158) that contains two glucagon-like sequences. The only proglucagon derived pancreatic peptide with known biological activity is glucagon. In the small intestine, the main products of proglucagon are (a) enteroglucagon (PG amino acids 1-69), which includes the glucagon sequence of amino acids, (b) GLP-1 (PG amino acids 78-107), and (c) GLP-2 (PG amino acids 126-158). C. .O slashed.rskov et al., Proglucagon Products in Plasma of Noninsulin-dependent Diabetics and Nondiabetic Controls in the Fasting State and after Oral Glucose and Intravenous Arginine, 87 J. Clin. Invest. 415 (1991). A variant of GLP-1(7-36)amide, termed GLP-1(7-37), has been shown to have indistinguishable biological effects and metabolic rates in healthy individuals, D. Gefel et al., Glucagon-Like Peptide-I Analogs: Effects on Insulin Secretion and Adenosine 3',5'-Monophosphate Formation, 126 Endocrinology 2164 (1990); C. .O slashed.rskov et al., Biological Effects and Metabolic Rates of Glucagonlike Peptide-1 7-36 Amide and Glucagonlike Peptide-1 7-37 in Healthy Subjects Are Indistinguishable, 42 Diabetes 658 (1993), but GLP-1(7-36)amide is the naturally occurring form in humans, C. .O slashed.rskov et al., Complete Sequences of Glucagon-like Peptide-1 from Human and Pig Small Intestine, 264 J. Biol. Chem. 12826 (1989). It has long been believed that an endocrine transmitter produced in the gastrointestinal tract, or incretin, stimulates insulin secretion in response to food intake. Since GLP-1(7-36)amide is released during a meal and after oral glucose administration and potentiates glucose-induced insulin release, this peptide may be an important incretin. J. M. Conlon, Proglucagon-derived Peptides: Nomenclature, Biosynthetic Relationships and Physiological Roles, 31 Diabetologia 563 (1988); J. J. Hoist et al., Truncated Glucagon-like Peptide 1, an Insulin-releasing Hormone from the Distal Gut, 211 FEBS Lett. 169 (1987); M. Gutniak et al., Antidiabetogenic Effect of Glucagon-like Peptide-1 (7-36)amide in Normal Subjects and Patients with Diabetes Mellitus, 326 N. Engl. J. Med. 1316 (1992).
An improved treatment regime for NIDDM patients exhibiting a secondary failure to sulfonylurea should give a satisfactory metabolic control without creating marked hyperinsulinemia. Until now, there have been no other serious candidates for a drug that can be used as such a treatment. Glucagon-like insulinotropic peptides, such as GLP-1(7-36)amide, appear to be the most promising treatment of diabetes. J. Eng, U.S. Pat. No. 5,424,286; S. E. Bjorn et al., WO 9517510; J. A. Galloway et al., EP 658568; H. Agerbk et al., WO 9505848; D. E. Danley et al., EP 619322; G. C. Andrews, WO 9325579; O. Kirk et al., WO 9318785; D. I. Buckley et al., WO 9111457; J. F. Habener, U.S. 5,118,666; J. F. Habener, WO9011296; J. F. Habener, WO8706941; J. F. Habener, U.S. Pat. No. 5,120,712. It has been found previously that the combination therapy of a GLIP and a sulfonyl urea exerts a synergistic effect on glycemia and insulin release. S. Efendic et al., WO 9318786.
R. W. Baker et al., U.S. Pat. No. 5,362,496, disclose oral dosage forms for transmucosal administration of nicotine for smoking cessation therapy. Such dosage forms include a lozenge, capsule, gum, tablet, ointment, gel, membrane, and powder, which are typically held in contact with the mucosal membrane and disintegrate or dissolve rapidly to allow immediate absorption. J. Kost et al., U.S. Pat. No. 4,948,587, disclose enhancement of transbuccal drug delivery using ultrasound. F. Theeuwes et al., U.S. Pat. No. 5,298,017, describes electrotransport of drugs, including peptides, through buccal membrane. J. L. Haslam et al., U.S. Pat. No. 4,478,822, teaches a drug delivery system that can be used for buccal delivery wherein the drug is combined with a polymer that is liquid at room temperature and semisolid or a gel at body temperature. T. Higuchi et al., U.S. Pat. No. 4,144,317, discloses a shaped body for drug delivery wherein the drug is contained in an ethylene-vinyl acetate copolymer. A. Zaffaroni, U.S. Pat. No. 3,948,254, describes buccal drug delivery with a device having a microporous wall surrounding a closed reservoir containing a drug and a solid drug carrier. The pores contain a medium that controls the release rate of the drug.
In view of the foregoing, it will be appreciated that compositions and methods for prolonged buccal delivery of glucagon-like insulinotropic peptides, such as GLP-1(7-36)amide, would be significant advancements in the art.